This project is focused on the identification of physiologically critical functions and mechanisms of action of NF-kB transcription factors and their regulators in health and disease. NF-kB is a family of related dimeric transcription factors that serve as primary intracellular mediators during innate and adaptive immune responses. In addition, and importantly, dysregulation of NF-kB plays a major role in inflammatory and autoimmune diseases as well as in numerous tumors. It is thus imperative to understand the functions and mechanisms of action of NF-kB factors, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing dysregulated NF-kB. To identify physiologic roles we make use of mouse models engineered to lack components of the NF-kB transcription factor family or their regulators as well as models in which the NF-kB factors can be selectively activated. Our work is focused on alternatively and classically activated NF-kB factors and especially on Bcl-3. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 is an atypical IkB family member that functions as nuclear regulator of NF-kB activity. In FY 2012 we have succeeded to develop lines of mice with which we can ablate Bcl-3 in a cell-specific manner. These mice can now be evaluated as to effects on development of the immune system, responses to pathogenic challenge and pathogenesis in experimentally induced inflammation, contexts in which a role for Bcl-3 has been implicated, but in which Bcl-3s mechanisms of actions are not understood. In FY 2012 we have also succeeded in generating mice in which multiple NF-kB factors can be cell-specifically activated and preliminary analysis reveals an unexpected hyperproliferative phenotype of some epithelial cells, which is currently under investigation.